The identity and properties of cancer stem cells (CSCs) has been a field of intense study in recent years. Evidence is accumulating that tumors are a heterogeneous mixture of cells with different biological properties. The isolation of distinct cell populations with the unique ability to initiate tumor growth has been reported for numerous hematologic malignancies and solid tumors. However, inconsistencies have emerged in the use of specific cell surface markers to prospectively identify CSCs. For example, disparate findings on stem cell phenotype have been reported for leukemias, pancreatic, colorectal, brain and breast cancers (Reviewed in Brennan and Matsui 2009). Furthermore, estimates of CSC frequency vary dramatically between tumor types and patients. The role of CSCs in maintaining the growth of an established tumor or in re-initiating a tumor after chemotherapy either at a primary or distant site, remains to be determined.
For most cancer patients, disease relapse after chemotherapy is a major cause of mortality. Accordingly, a better understanding of the tumor re-initiating cells (TRICs) responsible for relapse is needed in order to better treat patients who have experienced a recurrence of cancer after initially responding to chemotherapeutic treatment. This is particularly relevant for non-small cell lung cancer (NSCLC) because more than two thirds of NSCLC patients are not candidates for surgical resection. Most patients present with advanced disease and are treated with chemotherapy, radiation or a combination of the two (lung cancer principles and practice). However, the 5 year survival rate for locally advanced disease remains at 23.7% and at 3.5% for advanced disease despite good initial responses to therapy (Horner et al. SEER).
Deregulation of EGFR signaling via overexpression or activating mutations has been shown to be a frequent event in NSCLC (reviewed in Dahabreh et al., 2010). EGFR is the prototypical member of the HER family of tyrosine kinases, which includes EGFR (Her1), Her2, Her3 and Her4. Her2 lacks a functional ligand binding domain (Graus-Porta 1997) and Her3 lacks tyrosine kinase activity (Guy 1994), so these receptors must act as heterodimers. Recent evidence shows that other Her family members may also play a role in NSCLC. However their contributions to the disease are less well characterized and studies have often focused on their interactions with EGFR activation (Kuyama et al. 2008, Hirsch 2009, Zhou 2006, Johnson 2006, Ding 2008).
Neuregulin is a ligand for the Her3 and Her4 receptor tyrosine kinases. There are four known members of the neuregulin family, NRG1, NRG2, NRG3, and NRG4 (Falls 2003). The NRG1 transcript undergoes extensive alternative splicing resulting in at least 15 different isoforms. All active isoforms share an EGF-like domain that is necessary and sufficient for activity (Holmes 1992, Yarden 1991). NRG1 autocrine signaling has been shown to regulate lung epithelial cell proliferation (Jinbo 2002) and to play a role in human lung development (Patel 2000) and has been implicated in insensitivity of NSCLC to EGFR inhibitors (Zhou 2006).
The need exists to provide therapeutics effective in treating resistant cancers and patients who have experienced a recurrence of cancer.